Key result
Migration of the isobutyl side chain in biphenyl AT2 receptor ligands interconverted functional activity between agonism and antagonism, independent of the methylene imidazole position.
Provides a structural blueprint for tuning AT2 receptor pharmacology; leaves open whether these.
Migration of the methylene imidazole side chain in the first reported selective drug-like AT2 receptor agonist C21/M024 (1) delivered the AT2 receptor antagonist C38/M132 (2). We now report that the AT2 receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein.
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Wallinder et al. (2014) conducted a letter in In vitro AT2 receptor binding and functionality. Biphenyl AT2 receptor ligands (compounds 3-6) vs. Ang II, PD 123,319 was evaluated on AT2 receptor affinity (Ki) and neurite outgrowth in NG108-15 cells. Migration of the isobutyl side chain in biphenyl AT2 receptor ligands interconverted functional activity between agonism and antagonism, independent of the methylene imidazole position.
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